tbuckley/cabot-search huggingface dataset:
IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases
Authors: Stéphanie Lavazais, Manja Jargosch, Sonia Dupont, Frédéric Labéguère, Christel Menet, Catherine Jagerschmidt, Frenz Ohm, Laszlo Kupcsik, Isabelle Parent, Céline Cottereaux, Florence Marsais, Line Oste, An Van de Water, Thierry Christophe, Steve De Vos, Padraic Fallon, Felix Lauffer, Philippe Clément-Lacroix, Kilian Eyerich, Reginald Brys
Journal: Science Translational Medicine (2023)

Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23–, IL-33–, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy
Authors: Fan Yang, Duo Zhang, Haowen Jiang, Jiangbin Ye, Lin Zhang, Stephen J. Bagley, Jeffery Winkler, Yanqing Gong, Yi Fan
Journal: Science Translational Medicine (2023)

T cell–based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell–based immunotherapy in GBM and other solid tumors that warrants further investigation.
Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study
Authors: Martin Hoenigl, Jon Salmanton-García, Matthias Egger, Jean-Pierre Gangneux, Tihana Bicanic, Sevtap Arikan-Akdagli, Ana Alastruey-Izquierdo, Nikolai Klimko, Aleksandra Barac, Volkan Özenci, Eelco F J Meijer, Nina Khanna, Matteo Bassetti, Riina Rautemaa-Richardson, Katrien Lagrou, Kai-Manuel Adam, Emin Halis Akalin, Murat Akova, Valentina Arsic Arsenijevic, Avinash Aujayeb, Ola Blennow, Stéphane Bretagne, François Danion, Blandine Denis, Nick Alexander de Jonge, Guillaume Desoubeaux, Lubos Drgona, Nurettin Erben, Andrea Gori, Julio García Rodríguez, Carolina Garcia-Vidal, Daniele Roberto Giacobbe, Anna L Goodman, Petr Hamal, Helena Hammarström, Cristina Toscano, Fanny Lanternier, Cornelia Lass-Flörl, Deborah E A Lockhart, Thomas Longval, Laura Loughlin, Tadeja Matos, Malgorzata Mikulska, Manjusha Narayanan, Sonia Martín-Pérez, Juergen Prattes, Benedict Rogers, Laman Rahimli, Maite Ruiz, Emmanuel Roilides, Michael Samarkos, Ulrike Scharmann, Uluhan Sili, Oguz Resat Sipahi, Alena Sivakova, Joerg Steinmann, Janina Trauth, Ozge Turhan, Jens Van Praet, Antonio Vena, P Lewis White, Birgit Willinger, Anna Maria Tortorano, Maiken C Arendrup, Philipp Koehler, Oliver A Cornely, Mario Tumbarello, Alida Fe Talento, Alba C Ruiz, Zdenek Racil, Igor Stoma, Maria Calbacho, Eric Van Wijngaerden, Júlia Henriques, Harriett Jordan, Valentina Ferroni, Ozlem Koyuncu Ozyurt, Christopher Milacek, Robert Krause, Christoph Zurl, Matthijs Backx, Ang Li, Raphael Seufert, Rok Tomazin, Yael Blankenheim, Julio Dávila-Valls, Paloma García-Clemente, Tomas Freiberger, Jochem Buil, Jacques F Meis, Deniz Akyol, Hélène Guegan, Clare Logan
Journal: The Lancet Infectious Diseases (2023)
Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose
Authors: Bruno Andraus Filardi, Valter Silva Monteiro, Pedro Vellosa Schwartzmann, Vivian do Prado Martins, Luis Eduardo Rosa Zucca, Gabriela Crispim Baiocchi, Amyn A. Malik, Julio Silva, Anne M. Hahn, Nicholas F. G. Chen, Kien Pham, Eddy Pérez-Then, Marija Miric, Vivian Brache, Leila Cochon, Rafael A. Larocca, Roberto Della Rosa Mendez, Douglas Bardini Silveira, Aguinaldo Roberto Pinto, Julio Croda, Inci Yildirim, Saad B. Omer, Albert I. Ko, Sten H. Vermund, Nathan D. Grubaugh, Akiko Iwasaki, Carolina Lucas, Chantal B. F. Vogels, Mallery Breban, Tobias R. Koch, Chrispin Chaguza, Irina Tikhonova, Christopher Castaldi, Shrikant Mane, Bony De Kumar, David Ferguson, Nicholas Kerantzas, David Peaper, Marie L. Landry, Wade Schulz
Journal: Science Translational Medicine (2023)

The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2–related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients &gt;50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.
CD19-targeted CAR T cells in refractory antisynthetase syndrome
Authors: Fabian Müller, Sebastian Boeltz, Johannes Knitza, Michael Aigner, Simon Völkl, Soraya Kharboutli, Hannah Reimann, Jule Taubmann, Sascha Kretschmann, Wolf Rösler, Bernhard Manger, Jochen Wacker, Dimitrios Mougiakakos, Samir Jabari, Rolf Schröder, Michael Uder, Frank Roemer, Gerhard Krönke, Andreas Mackensen, Georg Schett
Journal: The Lancet (2023)
Peptide microarray IgM and IgG screening of pre-SARS-CoV-2 human serum samples from Zimbabwe for reactivity with peptides from all seven human coronaviruses: a cross-sectional study
Authors: Jordan Ashworth, Dayna Mathie, Fiona Scott, Yuvaraj Mahendran, Mark Woolhouse, Oda Stoevesandt, Takafira Mduluza, Francisca Mutapi
Journal: The Lancet Microbe (2023)
Concussion through my eyes: a qualitative study exploring concussion experiences and perceptions of male English blind footballers
Authors: Richard Weiler, Osman Hassan Ahmed, Willem van Mechelen, Evert Verhagen, Caroline Bolling
Journal: British Journal of Sports Medicine (2023)

Athletes with impairments play sports with a risk of sustaining head injuries and concussions. However, the scientific knowledge needed to improve care is lacking. This qualitative study explores English blind 5-a-side footballers' perceptions of concussion, concussion risks and prevention to improve para concussion care.Nine semi-structured interviews were conducted with male English blind footballers (six current and three retired). Data were analysed by thematic analysis using a six-stage approach.Blind footballers were not sure about the number of concussions they had sustained. They lacked an understanding of what to experience when concussed, and they perceived the diagnosis and experience of a concussion to be different for a person without vision. Perceived concussion severity and previous concussion experiences were key concepts affecting their concussion reporting behaviours. Participants mentioned spatial orientation and sleep are important to function in daily life and were affected by concussions. However, these factors are not adequately included in current assessment tools or clinical guidance for sports-related concussions.Blind footballers suggested the quality and accuracy of reported concussions were impacted by lack of concussion experience, knowledge and concomitant impairment. A better understanding of concussion symptoms and injury mechanisms will improve concussion reporting for athletes with visual impairments. These athlete insights should guide future studies and para sports governing body initiatives to improve concussion reporting, diagnosis and management in para athletes.
Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer
Authors: Eva Karamitopoulou, Anna Silvia Wenning, Animesh Acharjee, Inti Zlobec, Pauline Aeschbacher, Aurel Perren, Beat Gloor
Journal: Gut (2023)

Objective Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence. Design PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK) + CD45 − (tumour cells); CD45 + PanCK - (leucocytes) and PanCK - CD45 - (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel. Results No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin + fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP + fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis. Conclusions Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.
Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets
Authors: Mary K Crow
Journal: Annals of the Rheumatic Diseases (2023)

Research elucidating the pathogenesis of systemic lupus erythematosus (SLE) has defined two critical families of mediators, type I interferon (IFN-I) and autoantibodies targeting nucleic acids and nucleic acid-binding proteins, as fundamental contributors to the disease. On the fertile background of significant genetic risk, a triggering stimulus, perhaps microbial, induces IFN-I, autoantibody production or most likely both. When innate and adaptive immune system cells are engaged and collaborate in the autoimmune response, clinical SLE can develop. This review describes recent data from genetic analyses of patients with SLE, along with current studies of innate and adaptive immune function that contribute to sustained IFN-I pathway activation, immune activation and autoantibody production, generation of inflammatory mediators and tissue damage. The goal of these studies is to understand disease mechanisms, identify therapeutic targets and stimulate development of therapeutics that can achieve improved outcomes for patients.
Emerging trends in organ-on-a-chip systems for drug screening
Authors: Yanping Wang, Yanfeng Gao, Yongchun Pan, Dongtao Zhou, Yuta Liu, Yi Yin, Jingjing Yang, Yuzhen Wang, Yujun Song
Journal: Acta Pharmaceutica Sinica B (2023)

New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an
Carbapenemase-loaded outer membrane vesicles protect Pseudomonas aeruginosa by degrading imipenem and promoting mutation of antimicrobial resistance gene
Authors: Xiaotuan Zhang, Changrui Qian, Miran Tang, Weiliang Zeng, Jingchun Kong, Cheng Fu, Chunquan Xu, Jianzhong Ye, Tieli Zhou
Journal: Drug Resistance Updates (2023)

To investigate the effect of Klebsiella pneumoniae carbapenemase (KPC)-loaded outer membrane vesicles (OMVs) in protecting Pseudomonas aeruginosa against imipenem treatment and its mechanism. The OMVs of carbapenem-resistant Klebsiella pneumonia (CRKP) were isolated and purified from the supernatant of bacterial culture by using ultracentrifugation and Optiprep density gradient ultracentrifugation. The transmission electron microscope, bicinchoninic acid, PCR and carbapenemase colloidal gold assays were applied to characterize the OMVs. Bacterial growth and larvae infection experiments were performed to explore the protective function of KPC-loaded OMVs for P. aeruginosa under imipenem treatment. Ultra-performance liquid chromatography, antimicrobial susceptibility testing, whole-genome sequencing and bioinformatics analysis were used to investigate the mechanism of P. aeruginosa resistance phenotype mediated by OMVs. CRKP secreted OMVs loaded with KPC, which protect P. aeruginosa from imipenem through hydrolysis of antibiotics in a dose- and time-dependent manner. Furthermore, carbapenem-resistant subpopulations were developed in P. aeruginosa by low concentrations of OMVs that were confirmed to inadequately hydrolyze imipenem. Interestingly, none of the carbapenem-resistant subpopulations obtained the exogenous antibiotic resistance genes, but all of them possessed OprD mutations, which was consistent with the mechanism of P. aeruginosa induced by sub-minimal inhibitory concentrations of imipenem. OMVs containing KPC provide a novel route for P. aeruginosa to acquire an antibiotic-resistant phenotype in vivo.
Automatic uncertainty-based quality controlled T1 mapping and ECV analysis from native and post-contrast cardiac T1 mapping images using Bayesian vision transformer
Authors: Tewodros Weldebirhan Arega, Stéphanie Bricq, François Legrand, Alexis Jacquier, Alain Lalande, Fabrice Meriaudeau
Journal: Medical Image Analysis (2023)

Deep learning-based methods for cardiac MR segmentation have achieved state-of-the-art results. However, these methods can generate incorrect segmentation results which can lead to wrong clinical decisions in the downstream tasks. Automatic and accurate analysis of downstream tasks, such as myocardial tissue characterization, is highly dependent on the quality of the segmentation results. Therefore, it is of paramount importance to use quality control methods to detect the failed segmentations before further analysis. In this work, we propose a fully automatic uncertainty-based quality control framework for T1 mapping and extracellular volume (ECV) analysis. The framework consists of three parts. The first one focuses on segmentation of cardiac structures from a native and post-contrast T1 mapping dataset (n=295) using a Bayesian Swin transformer-based U-Net. In the second part, we propose a novel uncertainty-based quality control (QC) to detect inaccurate segmentation results. The QC method utilizes image-level uncertainty features as input to a random forest-based classifier/regressor to determine the quality of the segmentation outputs. The experimental results from four different types of segmentation results show that the proposed QC method achieves a mean area under the ROC curve (AUC) of 0.927 on binary classification and a mean absolute error (MAE) of 0.021 on Dice score regression, significantly outperforming other state-of-the-art uncertainty based QC methods. The performance gap is notably higher in predicting the segmentation quality from poor-performing models which shows the robustness of our method in detecting failed segmentations. After the inaccurate segmentation results are detected and rejected by the QC method, in the third part, T1 mapping and ECV values are computed automatically to characterize the myocardial tissues of healthy and cardiac pathological cases. The native myocardial T1 and ECV values computed from automatic and manual segmentations show an excellent agreement yielding Pearson coefficients of 0.990 and 0.975 (on the combined validation and test sets), respectively. From the results, we observe that the automatically computed myocardial T1 and ECV values have the ability to characterize myocardial tissues of healthy and cardiac diseases like myocardial infarction, amyloidosis, Tako-Tsubo syndrome, dilated cardiomyopathy, and hypertrophic cardiomyopathy.
Tumor-infiltrating lymphocytes as a predictive biomarker of cutaneous immune-related adverse events after immune checkpoint blockade in patients with advanced melanoma
Authors: Michael R. Stephens, Maria S. Asdourian, Ted V. Jacoby, Nishi Shah, Leah L. Thompson, Tracey Otto, Yevgeniy R. Semenov, Kerry L. Reynolds, Ryan J. Sullivan, Ruth K. Foreman, Steven T. Chen
Journal: Journal of the American Academy of Dermatology (2023)
NHS staff join aid workers in Turkey
Authors: Gareth Iacobucci
Journal: BMJ (2023)

A week on from the devastating earthquakes that hit Turkey and Syria, NHS health workers have begun to arrive in the area to staff the temporary hospitals such as this one (main image) in the Islahiye district of Gaziantep, Turkey.The first wave of 18 UK doctors, nurses, and paramedics will work at the hospital, run by the independent non-governmental organisation UK-Med.The 67 sq m tented polyclinic has its own infrastructure, staff, housing, medicines, supplies, and water sanitation.The facility can treat as many as 100 patients a day as outpatients and will focus on minor trauma, stabilisation, outpatient care, obstetrics and gynaecology, paediatrics, and general practice.Inset images: (1) A rescuer cradles a child, who was pulled from the rubble in the rebel held area of Idlib province, Syria; (2) Tedros Adhanom Ghebreyesus, WHO's director general, visits Alrazi Hospital in Aleppo, Syria, last weekend; (3) Fatma, a 2 year old girl, is rescued from the rubble 88 hours after the first earthquake hit Hatay, the southernmost province of Turkey
Immunophenotypic aberrant hematopoietic stem cells in myelodysplastic syndromes: a biomarker for leukemic progression
Authors: Margot F. van Spronsen, Diana Hanekamp, Theresia M. Westers, Noortje van Gils, Eline Vermue, Arjo Rutten, Joop H. Jansen, Birgit I. Lissenberg-Witte, Linda Smit, Gerrit J. Schuurhuis, Arjan A. van de Loosdrecht
Journal: Leukemia (2023)

Abstract Myelodysplastic syndromes (MDS) comprise hematological disorders that originate from the neoplastic transformation of hematopoietic stem cells (HSCs). However, discrimination between HSCs and their neoplastic counterparts in MDS-derived bone marrows (MDS-BMs) remains challenging. We hypothesized that in MDS patients immature CD34 + CD38 − cells with aberrant expression of immunophenotypic markers reflect neoplastic stem cells and that their frequency predicts leukemic progression. We analyzed samples from 68 MDS patients and 53 controls and discriminated HSCs from immunophenotypic aberrant HSCs (IA-HSCs) expressing membrane aberrancies (CD7, CD11b, CD22, CD33, CD44, CD45RA, CD56, CD123, CD366 or CD371). One-third of the MDS-BMs (23/68) contained IA-HSCs. The presence of IA-HSCs correlated with perturbed hematopoiesis (disproportionally expanded CD34 + subsets beside cytopenias) and an increased hazard of leukemic progression (HR = 25, 95% CI: 2.9–218) that was independent of conventional risk factors. At 2 years follow-up, the sensitivity and specificity of presence of IA-HSCs for predicting leukemic progression was 83% (95% CI: 36–99%) and 71% (95% CI: 58–81%), respectively. In a selected cohort ( n = 10), most MDS-BMs with IA-HSCs showed genomic complexity and high human blast counts following xenotransplantation into immunodeficient mice, contrasting MDS-BMs without IA-HSCs. This study demonstrates that the presence of IA-HSCs within MDS-BMs predicts leukemic progression, indicating the clinical potential of IA-HSCs as a prognostic biomarker.